Active Pharmaceutical Ingredients (API)

Good Manufacturing Practice (GMP) expectations for Active Pharmaceutical Ingredients (APIs)
In October 2005 new legislation was passed in the European Union requiring that Active Pharmaceutical Ingredients (API) used as starting materials in dose form pharmaceutical manufacture must have been manufactured in compliance with GMP. The relevant legislation is:

• Amended EU medicines legislation – Directive 2004/27/EC (2001/83/EC as amended).
• This was transposed into law in each member state (in UK as Statutory Instrument S.I. 2005/2789, October 2005).

Article 46(f) of 2004/27/EC introduced an obligation (by law via S.I. 2005/2789 in UK) for Manufacturing Authorisation holders to use as starting materials only active substances, which have been manufactured in accordance with the detailed guidelines on Good Manufacturing Practice for active substances.

In addition, from this date marketing authorisation applications and variations to change the source of the active substances used as starting materials have had to be supported by a declaration of GMP compliance of the active substance manufacturer by a Qualified Person (QP) of the dosage form manufacturer.

The legislation applies to all registered APIs. It is a requirement for all registered drug products that an active ingredient is named on the Marketing Authorisation Application. In some cases materials named as the active ingredient may be commercially manufactured for uses other than in drug products. These are commonly so called atypical actives.

Difficulties facing dose form manufacturers in assuring GMP of certain ‘Atypical’ APIs are understood by MHRA. It may be that the primary use of the material is not for drug product use and the primary use may not require standards fully equivalent to GMP. The pharmaceutical user of the material may be a very small customer and does not have the necessary influence to demand or guide the manufacturer toward full GMP manufacturing standards. To date MHRA has taken a pragmatic approach to GMP compliance of these materials and as such has considered each case on its own merits.

Guidance on expectations of GMP for APIs and atypical API GMP compliance is available below:
› API focussed MHRA inspections at dosage form manufacturers (60Kb)
› GMP expectations of Non Traditional APIs (10Kb)